[unreadable] [unreadable] The objective of this application is to identify the role of p21-Activated Kinase 1 (Pak1) in molecular pathways responsible for specific cellular and biochemical phenotypes associated with plexiform neurofibroma formation resulting from the genetic disorder Neurofibromatosis Type I (NF1). Neurofibromatosis is the result of mutations at the NF1 locus, which encodes the large GTPase activating protein neurofibromin. Neurofibromin is a negative regulator of the proto-oncogene p21 Ras(Ras). Ras hyperactivation is the molecular basis of NF1 associated phenotypes, and our group has demonstrated that restoration of Ras signaling to wild type levels can correct NF1 associated phenotypes in vitro and in vivo. NF1 is a common, pandemic, inherited disease that affects over 200,000 patients in North America, Europe, and Japan alone. Individuals with NF1 display a wide variety of pathologies; importantly, 15-40% of NF1 patients are affected by plexiform neurofibromas. Neurofibromas are complex tumors consisting of tumorgenic Schwann cells surrounded by endothelial cells, fibroblasts, and inflammatory mast cells. Recent evidence from our group indicates that the hematopoietic tumor microenvironment carries out a crucial function in the formation of plexiform neurofibromas. These tumors affect the peripheral nerves and commonly can be found in the face, limbs, or along the spinal nerve roots. These lesions contribute significantly to the morbidity and mortality associated with NF1. Currently, no medical therapies exist for treating neurofibromas. In keeping with our long term goal of detecting potential molecular targets for medical therapies to treat human plexiform neurofibromas, we have identified the kinase Pak1 as a possible downstream intermediary of Ras signaling in NF1 deficient cells. Therefore, by intercrossing mice heterozygous at Nf1 (the murine homolog of NF1) with Pak1-/- mice, we are able to test genetically, in vitro and in vivo, the hypothesis that inactivation of Pak1 would lead to correction of the gains of function phenotypes seen in Nf1 haploinsufficient cells. Further, we will determine the role of Pak1 in the development of neurofibromas, by utilizing a conditional Nf1 knockout mouse (Krox20Cre;Nf1flox/-) that is a reliable model of plexiform neurofibroma formation. These studies will provide insight into the causes of debilitating tumors related to a common genetic disease. No treatment for these tumors exists at this time, and this research could potentially lead to the development of medical therapies for these tumors. Preventing or reducing the size of these tumors could increase quality of life for tens of thousands of affected individuals each year. [unreadable] [unreadable] [unreadable]